Top Boehringer Ingelheim drug gets FDA approval in rare skin disease

 For many patients with generalized pustular psoriasis (GPP), the journey to diagnosis could take years, as doctors can mistake the incredibly rare skin condition for an infection. And when they do get diagnosed, there are only a few drugs — none officially approved — they can use to manage the painful flares that characterize the disease.

Boehringer Ingelheim just got the green light to change that for US patients.

The FDA has approved spesolimab, an IL-36R antibody, to treat GPP flares in adults. It will be marketed as Spevigo.

The German pharma emphasized in its release how the autoimmune disease can lead to life-threatening complications, such as heart failure, renal failure and sepsis.

“We recognize how devastating this rare skin disease can be for patients, their families and caregivers,” Carinne Brouillon, a member of Boehringer’s board of managing directors responsible for human pharma, said in a statement.

In a pivotal Phase II trial, slightly more than half of the patients — most of whom started with a high density of pustules on their body and impaired quality of life — showed no more visible pustules after 12 weeks of spesolimab.

The OK gives Boehringer a significant lead over AnaptysBio, which is developing a similar IL-36R antibody for the same indication, and could affect AnaptysBio’s recently revealed plans to out-license the drug.

Both companies, though, have been running into setbacks trying to test their drugs for other diseases. While Boehringer once touted spesolimab as a top program, just a few weeks ago it quietly shut down a small Phase II study in Crohn’s patients suffering from bowel obstructions, citing the current therapeutic landscape.

https://endpts.com/top-boehringer-ingelheim-drug-gets-fda-approval-in-rare-skin-disease/

Lowering the Cost of Insulin Could Be Deadly

 When I heard that my patient was back in the ICU, my heart sank. But I wasn’t surprised. Her paycheck usually runs short at the end of the month, so her insulin does too. As she stretches her supply, her blood sugar climbs. Soon the insatiable thirst and constant urination follow. And once her keto acids build up, her stomach pains and vomiting start. She always manages to make it to the hospital before the damage reaches her brain and heart. But we both worry that someday, she won’t.

The Inflation Reduction Act, passed last month, aims to help people like her by lowering the cost of insulin across America. Although efforts to expand protections to privately insured Americans were blocked in the Senate, Democrats succeeded in capping expenses for the drug among Americans on Medicare at $35 a month, offering meaningful savings for our seniors, some of whom will save hundreds of dollars a month thanks to the measure. In theory, the policy (and similar ones at the state level) will help the estimated 25 percent of Americans on insulin who have been forced to ration the drug because of cost, and will prevent some of the 600 annual American deaths from diabetic ketoacidosis, the fate from which I’m trying to save my patient.

Indeed, laws capping co-payments for insulin are welcome news both financially and medically to patients who depend on the drug for survival. However, in their current version, such laws might backfire, leading to even more diabetes-related deaths overall.

How could that be true? Thanks to the development of new drugs, insulin’s role in diabetes treatment has been declining over the past decade. It remains essential to the small percent of patients with type 1 diabetes, including my patient. But for the 90 percent of Americans with diabetes who have type 2, it should not routinely be the first-, second-, or even third-line treatment. The reasons for this are many: Of all diabetes medications, insulin carries the highest risk of causing dangerously low blood sugar. The medication most commonly comes in injectable form, so administering it usually means painful needle jabs. All of this effort is rewarded with (usually unwanted) weight gain. Foremost and finally, although insulin is excellent at tamping down high blood sugar—the hallmark of diabetes and the driver of some of its complications—it is not as impressive as other medications at mitigating the most deadly and debilitating consequences of the disease: heart attacks, kidney disease, and heart failure.

Large clinical trials have shown that two newer classes of diabetes medicines, SGLT2 inhibitors and GLP-1 receptor agonists, outperform alternatives (including insulin) in reducing the risk of these disabling or deadly outcomes. Giving patients these drugs instead of older options over a period of three years prevents, on average, one death for about every 100 treated. And SGLT2 inhibitors and GLP-1 receptor agonists pose less risk of causing dangerously low blood sugar, generally do not require frequent injections, and help patients lose weight. Based on these data, the American Diabetes Association now recommends SGLT2 inhibitors and GLP-1 receptor agonists be used before insulin for most patients with type 2 diabetes.

When a young person dies from diabetic ketoacidosis because they rationed insulin, the culprit is clear. But when a patient with diabetes dies of a heart attack, the absence of an SGLT2 inhibitor or GLP-1 receptor agonist doesn’t get blamed, because other explanations abound: their uncontrolled blood pressure, the cholesterol medication they didn’t take, the cigarettes they continued to smoke, bad genes, bad luck. But every year, more than 1,000 times more Americans die of heart disease than DKA, and of those 700,000 deaths, a good chunk are diabetes-related. (The exact number remains murky.) Diabetes is a major reason that more than half a million Americans depend on dialysis to manage their end-stage kidney disease, and that about 6 million live with congestive heart failure. The data are clear—SGLT2 inhibitors and GLP-1 receptor agonists could help reduce these numbers.

Still, uptake of these lifesaving drugs is sluggish. Only about one in 10 people with type 2 diabetes is taking them (fewer still among patients who are not wealthy or white). The main cause is simple and stupid: American laws prioritize profits and patents over patients. Because SGLT2 inhibitors and GLP-1 receptor agonists remain under patent protections, drug companies can charge exorbitant rates for them: hundreds if not thousands of dollars a month, sometimes even more than insulin. Doctors spend hours completing arduous paperwork in the hopes of persuading insurers to help our patients, but we’re frequently denied anyway. And even when we do succeed, many patients are left with painful co-payments and deductibles. The most maddening part is that despite their substantial up-front expense, these medications are quite cost-effective in the long run because they prevent pricey complications down the road.

This is where addressing the cost of insulin—and only insulin—becomes problematic. Doctors are forced daily to decide between the best medication for our patients and the medication that our patients can afford. Katie Shaw, a primary-care physician with a bustling practice at Johns Hopkins, where I’m a senior resident, told me that plenty of her patients can’t afford SGLT2 inhibitors and GLP-1 receptor agonists. In such instances, Shaw is forced to use older oral alternatives and occasionally insulin. “They’re better than nothing at all,” she said.

If the cost of insulin is capped on its own, insulin will be more likely to jump in front of SGLT2 inhibitors and GLP-1 receptor agonists in treatment plans. That will mean more disease, more disability, and more death from diabetes.

Medicare patients might avoid some of these effects thanks to provisions in the IRA allowing Medicare to negotiate drug prices and capping out-of-pocket spending on prescriptions at $2,000 a year. The law also guarantees price negotiations for a handful of medications, but SGLT2 inhibitors and GLP-1 receptor agonists won’t necessarily be on the list. And most Americans are not on Medicare. Already, Shaw said, the patients in her practice who tend to be least able to afford SGLT2 inhibitors and GLP-1 receptor agonists are working-class people with private insurance. Some health centers, including the one Shaw and I work at, enjoy access to a federal drug-discount program that can make patent-protected medications, including SGLT2 inhibitors and GLP-1 receptor agonists, more affordable for the uninsured. But most Americans without insurance aren’t so lucky.

It would be cruel to choose between a world in which more people with type 2 diabetes are nudged toward a drug that won’t stave off the most dangerous complications, and one in which those with type 1 diabetes are priced out of life. In place of capping the out-of-pocket cost of just insulin, lawmakers should cap the out-of-pocket cost of all diabetes medications. This will both protect Americans dependent on insulin and smooth SGLT2 inhibitors’ and GLP-1 receptor agonists’ path to their revolutionary public-health potential.

The argument for lowering the cost of these drugs for patients is the same as the argument for insulin affordability: that it is both foolish and inhumane to make lifesaving diabetes medications unaffordable when their use prevents costly and deadly downstream complications.

Patients like mine need affordable access to insulin. But even more need access to SGLT2 inhibitors and GLP-1 receptor agonists. If the laws stop at insulin, many Americans could die unnecessarily—not from inadequate access to insulin, but from preferential access to it.

Michael Rose is a senior resident in internal medicine and pediatrics at Johns Hopkins University School of Medicine.

https://www.theatlantic.com/health/archive/2022/09/diabetes-medication-insulin-cost/671333/

Top Med Schools Weed Out DEI-Skeptical Applicants

 The best medical schools in the country are weeding out applicants who are insufficiently devoted to the leftist creed of Diversity, Equity, and Inclusion (DEI), according to a new report released by the non-profit Do No Harm.

Do No Harm, a nonprofit dedicated to “protect[ing] healthcare from a radical, divisive, and discriminatory ideology,” conducted an analysis of medical school application processes which found that these selective institutions are raising an additional barrier to entry on top of the strenuous testing and grade requirements.

“A review of the admissions process at 50 of the top-ranked medical schools found that 36 asked applicants their views on, or experience in, DEI efforts,” reads the Do No Harm report, which was obtained by National Review. “Many were overt in asking applicants if they agreed with certain statements about racial politics and the causes of disparate health outcomes.”

According to the report, medical schools are asking these questions in order to “turn ideological support for health equity and social justice initiatives into a credential that increases an applicant’s chance of acceptance,” “screen out dissenters,” and “signal to all applicants that they are expected to support this new cause.”

“Top medical schools have woven their commitment to woke politics into their application process, asking future doctors to prove their commitment to divisive ideologies or risk being rejected from medical school.” concludes the report.

Dr. Stanley Goldfarb founded Do No Harm after serving as associate dean at the University of Pennsylvania Perelman School of Medicine. In his view, the use of ideologically slanted application questions will stunt the development of those applicants who do make it through the gauntlet to enter a top medical school.

“The questions posed in the secondary applications require a specific mindset and a well-defined political ideology for an applicant to succeed in their quest to enter medical school. This rigidity in thinking prevents real freedom of thought,” Goldfarb told National Review.

The questions identified in the report vary in their implicit assumptions and the extent to which they probe applicants. Some ask about the unique experiences and challenges that applicants may have faced, or name-check diversity and ask in very general terms about its importance.

Others are more direct. The University of Pittsburgh’s School of Medicine, for example, professes to be interested in combating all forms of systemic barriers” and entreats applicants to share their “thoughts on opposing… systemic racism, anti-LGBTQ+ discrimination, and misogyny.”

“How will you contribute?” the application asks.

The University of Texas Southwestern Medical School asks prospective attendees to “describe an interaction or experience that has made you more sensitive or appreciative of cultural differences, and/ or how you have committed yourself to understanding and aiding in the pursuit of equity and inclusion in your academic, professional or personal life.”

At the University of Minnesota, applicants are first told that “our country is reckoning with its history, racism, racial injustice, and especially anti-black racism.” Then they’re asked to share their “reflections on, experiences with, and greatest lessons learned about systemic racism.”

And at the University of Miami, applicants are bluntly queried about what they have “done to help identify, address and correct an issue of systemic discrimination?” None of the aforementioned schools responded to a request for comment.

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Goldfarb dismissed the idea that these questions are merely being used to deduce whether applicants have a baseline level of respect for people coming from various backgrounds, or greater purpose for pursuing a career in medicine.

“The classic question, ‘Why do you want to become a physician?’ could get at motivation without invoking race. There should not be a litmus test for students to show their progressive bona fides in order to qualify for medical school,” he said.

Goldfarb himself can tell his own story about political dogma in the medical field. Earlier this year, he was denounced by his former colleagues at UPenn after he sent a tweet questioning whether the underperformance of minority medical students is entirely attributable to discrimination.

For this crime, Goldfarb’s punishment was having his tweet called “racist” by the chair of the Medicine Department, who pledged in an email sent to the entire Perelman community to “continue to fight the biases and injustices that erode the health of our nation.”

A Change.org petition was started and circulated by Project Diversify Medicine, a kind of anti-Do No Harm, seeking to have his affiliation with the university as a professor emeritus severed.

Because he’s reached the end of his academic career, Goldfarb has explained the vitriol directed toward him as being driven by the fact that his detractors “know they can’t hurt” him. But for students trying to get into or thrive on medical school campuses, there’s much more to lose.

https://www.nationalreview.com/news/top-med-schools-weed-out-applicants-who-dont-support-dei-new-report-says/

Finding antigens that trigger specific immune cells

 A cell's secrets can be divulged by its surface, decorated with tens to hundreds of thousands of molecules that help immune cells determine friend from foe. Some of those protruding molecules are antigens that trigger the immune system to attack, but it can be difficult for scientists to identify those antigens, which often vary across individuals, in the molecular forest.

A team of Stanford scientists led by Polly Fordyce, an Institute Scholar at Sarafan ChEM-H, has developed a new method to faster and more accurately predict which antigens will lead to a strong immune response. Their approach, which was reported in Nature Methods on Sept. 5, could help scientists develop more effective cancer immunotherapies.

T cells, a class of immune cells, crawl along and squish past other cells as they patrol the body, using T cell receptors to molecularly read peptides, or short pieces of proteins -- which are cradled within larger proteins called major histocompatibility complexes (pMHCs) that project from cell surfaces. Healthy host cells display an array of pMHCs that do not trigger an immune response, but once T cells recognize disease-indicating peptides, they become activated to find and kill cells bearing these foreign signatures. Understanding how T cells sensitively distinguish these antigenic peptides from host peptides to avoid mistakenly killing host cells has long been a mystery.

"A T cell can detect a single antigenic peptide amongst a sea of 10,000 or 100,000 non-antigenic peptides being displayed on cell surfaces," said Fordyce, assistant professor of bioengineering and of genetics.

The key to selectivity is in the T cell crawl. T cells' sliding puts stress on the bonds between receptors and peptides, and in most cases, that extra stress is enough to break that bond. But sometimes, it has the opposite effect. Chris Garcia, co-author of the study and professor of molecular and cellular physiology and of structural biology, and others had already shown that the most antigenic peptides are those whose interactions with T cell receptors grow stronger in response to sliding.

"It's kind of like a Chinese finger trap," said Fordyce. "When you pull a bit at the receptor-antigen interaction, the binding actually lasts longer."

Cellular mimicry

Identifying the best antigen-receptor pairs requires simultaneously applying that sliding, or shear, force between a peptide and a T cell and measuring T cell activation, ideally thousands of times to get repeatable data for many possible peptide/T cell receptor pairs. But existing methods are time-intensive and can result in measuring only one peptide with hundreds of T cells in a day.

The study's first author, postdoctoral scholar Yinnian Feng, developed a trick that allows the team to measure 20 unique peptides interacting with thousands of T cells in less than five hours.

To make a simplified system that mimics cells with dangling peptides, they constructed small spherical beads from a material that expands upon heating and attached a few molecules of a given peptide-studded pMHC to their surfaces. After depositing a T cell atop each bead and waiting long enough for receptors to bind to the peptides, they then very slightly heated the bead. The bead's expansion increases the distance between tether points, and the corresponding stretching of the T cell mimics the force it would experience sliding along cells in the body. After exerting that force, the team then measured how active the T cells were.

They could do hundreds of individual experiments in parallel by using beads that are each labeled with a unique color, making it possible to track multiple different pMHCs. They took two sets of pictures tiling across each slide after each run: one set that tells them which pMHC a given bead is displaying and another that tells them how active each T cell atop that bead is. Cross-referencing those images tells them which antigens led to the strongest T cell responses.

In this demonstration of their platform, the team showed, with 21 unique peptides, that their results confirmed known activating and non-activating peptides for one T cell receptor and uncovered a previously unknown antigen that induced a strong T cell response. Working with the Garcia lab, they have also already begun to address a challenge in immunotherapy: the T cell receptors that form the highest affinity interactions with antigens in the lab are often also activated by non-antigenic peptides in the body, a dangerous side effect that leads to the killing of healthy cells. Using their technology, the team characterized T cell receptors engineered to specifically recognize tumor antigens without off-target reactivity. In future work, they plan to build libraries of over 1,000 peptides to uncover novel antigens.

They hope that this approach, which is quick and requires few cells, or an optimized form of it could one day be used to improve personalized immunotherapies.

"This platform can help improve efforts to engineer T cells that specifically target cancer cells, as well as determine which antigens are capable of potently activating a patient's own T cells to more effectively target cancer cells," said Fordyce.

Fordyce is a member of Stanford Bio-X, SPARK, and the Wu Tsai Neurosciences Institute, and is a Chan Zuckerberg Biohub investigator. Garcia is a member of Stanford Bio-X, the Stanford Cancer Institute, the Wu Tsai Neurosciences Institute, and a Howard Hughes Medical Institute investigator.

Xiang Zhao and Adam K. White are also authors of the paper.

The work was funded by a Stanford Bio-X Interdisciplinary Initiatives seed grant and the National Institutes of Health.

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Story Source:

Materials provided by Stanford University. Original written by Rebecca McClellan. Note: Content may be edited for style and length.

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Journal Reference:

1. Yinnian Feng, Xiang Zhao, Adam K. White, K. Christopher Garcia & Polly M. Fordyce. A bead-based method for high-throughput mapping of the sequence- and force-dependence of T cell activation. Nature Materials, 2022 DOI: 10.1038/s41592-022-01592-2

https://www.sciencedaily.com/releases/2022/09/220905113005.htm

Meta faces $402 million EU fine over Instagram's privacy settings for children

 Meta has been fined €405 million ($402 million) by the Irish Data Protection Commission for its handling of children’s privacy settings on Instagram, which violated Europe’s General Data Protection Regulation (GDPR). As Politico reports, it’s the second-largest fine to come out of Europe’s GDPR laws, and the third (and largest) fine levied against Meta by the regulator.

A spokesperson for the DPC confirmed the fine, and said additional details about the decision would be available next week. The fine stems from the photo sharing app’s privacy settings on accounts run by children. The DPC had been investigating Instagram over children’s use of business accounts, which made personal data like email addresses and phone numbers publicly visible. The investigation also covered Instagram’s policy of defaulting all new accounts, including teens, to be publicly viewable. 

“This inquiry focused on old settings that we updated over a year ago, and we’ve since released many new features to help keep teens safe and their information private," a Meta spokesperson told Politico in a statement. "Anyone under 18 automatically has their account set to private when they join Instagram, so only people they know can see what they post, and adults can’t message teens who don’t follow them. We engaged fully with the DPC throughout their inquiry, and we’re carefully reviewing their final decision.”

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The fine, which Meta could still appeal, comes as Instagram has faced intense scrutiny over its handling of child safety issues. The company halted work on an Instagram Kids app last year following a whistleblower’s claims that meta ignored its own research indicating the app can have a negative impact on some teens’ mental health. Since then, the app has added more safety features, including changing default settings on teen accounts to private.

https://www.engadget.com/meta-fined-405-million-euro-instagram-privacy-161348122.html

Zymeworks Releases ESMO Abstract for Phase 1 Study of Zanidatamab Zovodotin in Solid Cancers

Zymeworks Inc. announced the release of an abstract by ESMO with preliminary results from the company's Phase 1 study of zanidatamab zovodotin (ZW49), an investigational novel bispecific HER2 targeted antibody-drug conjugate. Results from the study entitled “Preliminary Results From a Phase 1 Study Using the Bispecific, Human Epidermal Growth Factor 2 (HER2)-targeting Antibody-drug Conjugate (ADC) zanidatamab zovodotin (ZW49) in Solid Cancers” will be presented by Komal Jhaveri, MD, FACP, Medical Oncologist, Memorial Sloan Kettering Cancer Center in NYC, in a mini-oral presentation on September 12 at 5:25 pm CEST during the ESMO meeting being held September 9-13, 2022, at the Paris Expo Porte de Versailles in Paris, France. In an ongoing Phase 1 study of 76 patients with HER2+ cancers including gastric (28%) and breast (22%) cancers, preliminary results show that the majority of treatment related adverse events (TRAEs) were Grade 1 or 2 and included keratitis (42%), alopecia (25%) and diarrhea (21%). https://www.marketscreener.com/quote/stock/ZYMEWORKS-INC-34658200/news/Zymeworks-Announces-Release-of-ESMO-Abstract-for-Phase-1-Study-of-Zanidatamab-Zovodotin-in-Solid-Can-41696630/

Leap to Present New Data from Combo Studies at ESMO

 Leap Therapeutics, Inc. announced the company will be presenting data in first-line patients with advanced gastroesophageal adenocarcinoma (GEA) from the DisTinGuish study, a Phase 2a clinical trial evaluating Leap's anti-Dickkopf-1 (DKK1) antibody, DKN-01, in combination with tislelizumab, BeiGene's anti-PD-1 antibody, and chemotherapy, at the European Society for Medical Oncology (ESMO) Congress 2022 being held on September 9-12. Safety and early efficacy data will be presented from the WAKING study, a multicenter Phase 2 non-randomized trial evaluating DKN-01 plus Tecentriq® (atezolizumab), Roche's anti-PD-L1 antibody, in patients with advanced oesophagogastric adenocarcinoma (OGA). Key Findings DisTinGuish: DKN-01 and tislelizumab plus CAPOX was well tolerated in first-line treatment for advanced GEA patients, with a safety profile consistent with previous reports.

https://www.marketscreener.com/quote/stock/LEAP-THERAPEUTICS-INC-33375941/news/Leap-Therapeutics-to-Present-New-Data-from-DisTinGuish-Study-of-DKN-01-Plus-Tislelizumab-and-WAKING-41696631/